Amino acid modulated extended release dosage form

ABSTRACT

Disclosed herein is a tableted oral extended release dosage form comprising a plurality of granules of an effective amount of a pharmaceutically active compound, at least one amino acid, and an intragranular polymer in which the granule is dispersed within a hydrophilic extragranular polymer matrix which is more rapidly hydrating than the intragranular polymer. The amino acid is selected for hydropathy characteristics depending on solubility characteristics of the active compound.

[0001] The present application is a continuation-in-part of U.S. patentapplication Ser. No. 09/467,169, filed Dec. 20, 1999.

FIELD OF THE INVENTION

[0002] The present invention is directed to an oral tablet containingpharmaceutically active compounds. The present invention findsparticular usefulness in producing controlled drug release and ease oftablet manufacture. In particular, the invention is directed to drugtablets having minimal “burst effect” and a more linear drug releaseprofile over an extended period of time.

BACKGROUND OF THE INVENTION

[0003] In traditional sustained release matrix systems, the drug isincorporated into a matrix consisting of either hydrophobic orhydrophilic materials such as polymers. The predominant mechanism ofdrug release from such systems is diffusion, resulting in curved releaseprofiles that can be described by square root of time kinetics. Suchrelease profiles are characterized by initial rapid release followed bya gradual decline in the rate of release, resulting in a prolonged“tailing off” in the late time phase. This “tailing off” is oftenaccompanied by incomplete dissolution. Furthermore, there is typicallyan initial rapid release described as a “burst effect” which isattributed to the initial rapid wetting and dissolution of drug on thesurface of the dosage form. This type of curved release profile may be adisadvantage for drugs that are to be absorbed throughout thegastrointestinal tract over an extended period of time at a controlledor constant rate. More specifically, the amount of drug available forabsorption, over a period of drug release, steadily decreases. This maynecessitate more frequent dosing compared to a dosage form that has amore linear drug release profile over an extended period of time.However, even in formulations that have a near zero order release, bursteffects are frequently seen. The burst effect can be expected to beespecially problematic as drug load increases, because by implicationthe concentration of drug at the tablet surfaces increases.

[0004] A number of approaches have been adopted to counteract thenatural diffusive processes which control mass transfer from compressedtablets into surrounding aqueous dissolution media and to limit theburst effect. In particular, several methods to achieve so-called “zeroorder” controlled release or constant rates of release and approximatelinear release profiles have been developed. These approaches includegeometric modifications of the tablet, resulting in control of thesurface area available for drug diffusion. Other examples include theuse of multiple layer tablets, osmotic pumps, and coated pie shaped andhemispherical tablets with strategically located un-coated portions ofsurface area.

[0005] Many of the above named systems are of great utility, howeverthey suffer shortcomings in that they are relatively costly andcomplicated to manufacture, often requiring multiple manufacturing stepsand specialized equipment.

[0006] In addition, osmotic pump systems and multiple layer systems tendto deliver the drug in linear fashion only to about 85% of the totaldrug loaded, with severe tailing off thereafter. In the case of oralosmotic systems, this effect may be ascribed to the exhaustion of thereservoir device and the loss of osmotic pressure. Also, theaforementioned devices are of limited usefulness for the controlleddelivery of large doses of medicament, for example more than 600 mg.,especially if the medicament is relatively water soluble. In such casesof high drug loading, the addition of an absolute minimum of ratecontrolling excipient is necessary to achieve a tablet size that can becomfortably swallowed. Additionally, the need to add relatively largeamounts of osmoagent and/or hydrophilic rate controlling swellingpolymer layers severely limits the maximum drug load achievable in suchsystems.

[0007] Thus there is a need for a simple monolithic matrix tablet thatis capable of delivering a high drug load irrespective of drugsolubility to approximate zero order release kinetics.

[0008] In recent years, the value of hydrophilic polymer based systemsemploying controlled release has been increasingly demonstrated with thepublication of numerous patents and research papers. Infield et al.,U.S. Pat. No. 5,393,765, describes a hydrophilic erodible monolithictablet formulation capable of approximating zero order drug releasebased on hydroxypropylmethyl cellulose and various erosion enhancingexcipients such as lactose and surfactants such as Pluronic®. Theseconstituents are mixed with a drug to form a matrix, and subsequentlytableted. When ingested, the Infield et al. matrix forms two layers, anouter layer of hydrated matrix and an inner layer of unchanged matrix.

[0009] While semi-synthetic cellulose derivatives have found wide use incontrolled release formulations, a number of polysaccharide basedexcipients have also been employed in oral controlled release systems.Polysaccharides which have been used as controlled release excipients,and have been employed on their own or in combination with otherexcipients, include chitosan, alginic acid, carrageenan, scleroglucan,and modified starch products.

[0010] Xanthan gum, a semi-synthetic polysaccharide of bacterial origin,has also received frequent attention as a controlled release material.The potential of xanthan gum alone has been evaluated, and a number ofstudies of xanthan gum in combination with alginic acid or guar gum havealso been published. Baichwal et al., U.S. Pat. Nos. 4,994,276,5,128,143, and Staniforth et al., U.S. Pat. No. 5,135,757, disclosecontrolled release excipient systems utilizing xanthan gum and asynergistically interacting polysaccharide such as locust bean gum orguar gum, along with secondary and tertiary components such assaccharides or other hydrophilic polymers. In these patents, it isspeculated that a synergistic interaction occurs between xanthan and thepolysaccharide gum resulting in an increased viscosity and gel strength.Based on similar principles of a synergistic interaction between xanthanand a gum, Baichwal, et al., U.S. Pat. No. 5,455,046, discloses asustained release dosage form suitable for insoluble drugs such asnifedipine by employing cross-linked heteropolysaccharides andpolysaccharides.

[0011] Guar, a natural galactomannan, obtained from the seeds ofCyanopsis tetragonolobus has found use in the pharmaceutical industry asa disintegrating and binding agent for tablets, as well as a suspending,thickening, and stabilizing agent for liquid and semi solid products.Guar gum has also been used in some extended release formulations andcombinations of xanthan gum and guar gum have been extensively studied.The studies indicate that in certain instances, large amounts ofhydroxypropylmethyl cellulose had to be added to guar gum to achieveacceptable sustained release formulations. Altaf et al. (1998) and Yu etal. (1998) published articles on a guar gum based sustained releaseformulation containing diltiazem which was shown to be equivalent invitro and in vivo to a commercial product (Dilacor XR®). However,neither of these two preparations achieved a predominantly zero orderrelease profile. Khurts, in U.S. Pat. No. 5,292,518, discloses prolongedrelease formulations consisting of gel forming dietary fiber, such asguar gum, a drug, a mineral salt, which releases a physiologicallyacceptable gas on ingestion, disintegrants and binders. Optionally,organic acids such as maleic and citric acid can be included to furtheraid disintegration.

[0012] Furthermore, guar gum has been found to undergo efficientenzymatic degradation in the human large intestine and has thereforebeen used as a carrier for colon specific drug delivery. Modifying guargum with borax or glutaraldehyde has been reported as an effective meansof producing cross linked polymers with limited swelling potential andincreased viscosity. The limited swelling and increased viscosityreportedly increases the potential for the polymer matrix to stay intactand release a minimum of drug until the colon is reached. Friend andWong, U.S. Pat. No. 5,811,388, disclose a simple formulation consistingof a drug useful for treating colonic disorders or a peptide drug thatcan be absorbed from the colon, and a hydrocolloid gum obtainable fromhigher plants, preferably guar gum. The authors mention the possibleinclusion of a host of substances that may serve to stabilize a peptideor protein drug, or aid in drug penetration of gastrointestinalmembranes and absorption.

[0013] Amino acids such as glycine find frequent use as plasticizers inpolymer film coatings, as buffering agents and excipients used in thestabilization and formulation of lyophilized products, injectables, nosedrops and oral solutions. For example, DL-leucine has been used as ahydrophilic lubricant. Ibsen, U.S. Pat. No. 5,288,500, discloses thepossible use of amino acids in combination with hydrophilic polymers toenhance rapid swelling in order to mask grittiness and taste informulations of granules that are to be rapidly dispersed in water priorto ingestion. Adesunloye, U.S. Pat. No. 5,874,106, discloses that aminoacids in combination with carboxylic acids such as citric acid, preventcross-linking in gelatin capsules. Finally, Thombre et al., U.S. Pat.No. 5,697,922, describe an osmotic device wherein solubility adjustingsubstances, which may simultaneously act as osmoagents, can be made intocoated macro particles. These solubility adjusting substances mayinclude ionizing substances, salts, surfactants or amino acids.

[0014] Though useful as dosage forms, the release profiles of many ofthe prior compositions are usually characterized by initial rapidrelease followed by a gradual decline in the rate of release, resultingin a “prolonged tailing off” in the late time phase. The “tailing off”often results in incomplete dissolution and failure to achieve 100% drugrelease. Furthermore, there is typically an initial “burst effect”,causing a relatively large amount of drug to be released early indissolution, which is attributed to the initial rapid wetting anddissolution of drug on the surface of the dosage form. Lastly, many suchsystems suffer practical shortcomings in that they are relatively costlyand complicated to manufacture, often requiring multiple manufacturingsteps and specialized equipment.

[0015] Kim et al., WO 99/21551, discloses a simple polymeric matrixtablet that is designed to deliver drugs over extended periods of time,while being relatively easy to manufacture. The drug is first granulatedwith a swellable polymer to form granules. The granules are thendispersed within a matrix of a more swellable, erodible polymer andcompressed to form a monolithic matrix tablet which is readilymanufactured on commercial high speed tabletting equipment. Kim et al.does not make use of amino acids to mediate polymer swelling anddissolution of the drug, and the solubility of the drug plays thegreatest role in determining the release profile and release duration.Therefore, Kim et al. is limited in application to highly soluble drugs.

[0016] The present invention provides an extended release dosage formfor simple monolithic matrix tablets capable of delivering a high drugload of pharmaceutically active substances according to zero orderrelease kinetics over an extended period of time, preferably 12 to 24hours, in which drug release is mediated by the inclusion of an aminoacid.

[0017] Definitions

[0018] As used herein the following terms have the definitions set forthbelow.

[0019] “Hydropathy” refers to a scale of solubility characteristicscombining hydrophobicity and hydrophilicity of amino acids. Moreparticularly this term refers to a sliding scale, similar to a pH scale,which assigns relative values which represent the relative balancebetween hydrophobic and hydrophilic components of an amino acid. Atypical scale is set forth in Pliska et al., J. Chromatog. 216, 79,1981, entitled Relative Hydrophobic Character of Amino Acid Side Chains,wherein glycine has a value of 0, representing a relatively equalbalance between hydrophobic and hydrophilic components and may bereferred to as relatively ‘neutral’, ‘balanced’, ‘slightly hydrophilic’;or ‘weakly hydrophobic’, iso-leucine has a positive value of 1.83 and isstrongly hydrophobic, and on the opposite end of the scale, asparticacid has a negative value of-2.15 and may be characterized as stronglyhydrophilic. Such a scale and the hydropathy characteristics describedherein are well known and understood by those skilled in the art.Representative values and hydropathy characteristics are set forth inTable 1.

[0020] “Monolithic” refers to tablets that do not require multiplelayers, special shapes, osmotic compartments and/or specializedcoatings, typically without joints or seams, and are capable of beingtableted on modern high speed tableting equipment.

SUMMARY OF THE INVENTION

[0021] The present invention provides an oral extended release dosageform comprising a plurality of granules of a pharmaceutically activecompound granulated with at least one amino acid and an intragranularpolymer. The granules are dispersed within a hydrophilic extragranularpolymer to form a monolithic matrix. The extragranular polymer is morerapidly hydrating than the intragranular polymer in order to approximate100% release of the active compound while maintaining a linear releaseprofile and minimizing the complication and cost of manufacture ofcompressed monolithic tablets. The amino acid is selected for hydropathycharacteristics which depend on the solubility characteristics of theactive compound.

[0022] This invention also comprises a process for making a tabletedoral extended release dosage form comprising mixing a pharmaceuticallyactive compound with an intragranular polymer and at least one aminoacid; granulating the mixture to form granules; blending the resultinggranules with a more rapidly hydrating extragranular polymer to dispersethe granules within the matrix of extragranular polymer, and compressingthe resulting blend to form a simple monolithic tablet whichapproximates zero order release of the pharmaceutically active agentover an extended period of time.

[0023] In its simplest form, the present invention is a pharmaceuticallyactive agent combined with an intragranular polymer and at least oneamino acid and granulated by any suitable means to form granules. Thegranules are then blended with and dispersed within an extragranularpolymer. The granulation may then be compressed to form an extendedrelease monolithic matrix tablet.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]FIGS. 1a and 1 b illustrate the effects of amino acids ondissolution rates of verapamil HCl formulations.

[0025]FIGS. 2a and 2 b illustrate the effects of amino acids ondissolution rates of nifedipine formulations.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides a formulation for the controlledrelease of drugs from a monolithic tablet. The oral extended releasedosage form comprises a plurality of granules of a pharmaceuticallyactive compound, granulated with at least one amino acid, and anintragranular polymer. The granules are then dispersed within ahydrophilic extragranular polymer. An important aspect of this inventionis the use of an extragranular polymer which more rapidly hydratesrelative to the intragranular polymer. The rapid hydration of theextragranular polymer assists in the approximation of a linear releaseprofile of the drug and facilitates near 100% dissolution, whileextending the duration of release and reducing the burst effectfrequently encountered with extended release dosage forms. Although thelinear release rate can be tailored to fit the needs of each applicationby selecting polymers for different dissolution rates, as understood byone of ordinary skill in the art, a release time of 12 to 24 hours ismost preferred.

[0027] The intragranular polymer is combined with a pharmaceuticallyactive compound, and at least one amino acid to form granules. Theintragranular polymer may be one or more of the following: polyvinylacetate, a galactomannan polysaccharide such as hydroxypropyl guar, guargum, locust bean gum, pectin, gum acacia, gum tragacanth, karaya gum,cellulose ethers such as hydroxyproplymethyl cellulose (HPMC), as wellas other gums and cellulose ethers to be chosen by one of skill in theart for properties consistent with the teaching of this invention. Theintragranular polymer is preferably a galactomannan polysaccharide, mostpreferably guar gum (with a viscosity range of 75-6000 cps for a 1%solution at 25° C. in water and a particle size 10-300μm).

[0028] The intragranular polymer in the tablet is preferably present inamounts between 4% and 45% of the total dosage form weight. The specifictype of intragranular polymer and amount of intragranular polymer usedis chosen depending on the desired rate of drug release, viscosity ofthe polymer, the desired drug load, and the drug solubility. It is animportant aspect of this invention that the intragranular polymerhydrates less rapidly than the extragranular polymer. The relativedifference in hydration rates between the two polymers creates a lessviscous intragranular polymer and a more viscous extragranular polymer.Over time, the difference in viscosity contributes to the continuouserosion and disintegration of the tablet.

[0029] Amino acids are useful in this invention for two primary reasons.First, the amino acids are a factor in determining the viscosity of thepolymers. As noted above, over time the difference in viscosity betweenthe extragranular and intragranular polymers contributes to thecontinuous erosion and disintegration of the core, facilitating about100% release of the drug. Another important aspect of using an aminoacid in the granule is that the hydropathy of the amino acid may beexploited to modulate the solubility and release of a drug.

[0030] Thus, the amino acid is selected for hydropathy characteristicsdepending on the solubility characteristics of the active compound. Whenthe compound is at least sparingly water soluble, that is, for example,sparingly soluble, soluble or has a higher level of solubility, asdefined by the United States Pharmacopeia, an amino acid is utilizedwhich has a relatively equal balance between hydrophilic and hydrophobiccomponents, i.e. is neutral or balanced or within close proximity toneutrality, or is relatively more strongly hydrophilic.

[0031] For example, dissolution and release of soluble or sparinglysoluble ionizable drugs such as verapamil HCl can be controlled by theinclusion of one or more amino acids in the granules (FIG. 1a). Withoutsubscribing to a particular theory of drug release and dissolution, itis believed that the nature of the granulation process is such that asthe formulation components come into close molecular contact,granulation reduces the available surface area of the particles, thusreducing the initial rate of hydration. In the granulated formulations,there is sufficient time for the amino acid carboxyl (COOH—) groups andamino groups (NH₂/NH₃₊) to interact with hydroxyl groups on the polymer,thus mediating the swelling, viscosity, and gel properties of thepolymer and thereby exerting control on the swelling mediated drugdiffusion. Simultaneously, the amino acid carboxyl groups may alsointeract with suitable polar substituents on the drug molecule such assecondary or tertiary amines. Furthermore, the hydrophilic and ionicnature of amino acids results in their extensive hydration in aqueoussolution. Consequently, the amino acid promotes erosion, but alsocompetes with both the polymer and the drug for water uptake necessaryfor hydration and dissolution.

[0032] However, when the active compound is less than sparingly soluble,including active compounds which are slightly soluble to insoluble, acombination of at least two amino acids is utilized, one of which isstrongly hydrophobic, the other of which is relatively more hydrophilicthan the hydrophobic component, that is, about neutral or balanced tostrongly hydrophilic.

[0033] For example, the effect of a combination of amino acids in theintragranular polymer is further illustrated by the example ofnifedipine (a water insoluble drug) in FIG. 2(b). The figures illustratethat a particularly beneficial composition can be achieved bygranulating (1) nifedipine, (2) a hydrophobic amino acid, for exampleiso-leucine or phenylalanine, and (3) a weakly hydrophobic orhydrophilic amino acid, such as glycine, in which there the hydrophobicand hydrophilic components are relatively equal or balanced, and guar.The combination results in a marked increase in the dissolution rate ofnifedipine, thus allowing complete (near 100% of dose) dissolution in anapproximately linear fashion. Without subscribing to a particular modelof drug dissolution, it is believed that the above compositionfacilitates the close molecular association and possible weakcomplexation between the hydrophobic side chain of a stronglyhydrophobic amino acid such as iso-leucine and the strongly hydrophobicnifedipine molecules. Simultaneously, the less hydrophobic glycinemolecules are effectively able to intersperse themselves between, andable to interact with, the polar portions of the iso-leucine molecules.When exposed to water, the rapidly dissolving, more hydrophilic glycinemolecules “drag” with them, and increase the hydration of, the morehydrophobic iso-leucine molecules which are complexed with nifedipinemolecules by hydrophobic interaction.

[0034] The amino acid component of the granules may comprise anypharmaceutically acceptable α-amino or β-amino acids, salts of α- orβ-amino acids, or any combination thereof. Examples of suitable α-aminoacids are glycine, alanine, valine, leucine, iso-leucine, phenylalanine,proline, aspartic acid, glutamic acid, lysine, arginine, histidine,serine, threonine, cysteine, asparagine, and glutamine. An example of aβ-amino acid is β-alanine.

[0035] The type of amino acids used in the present inventionalternatively can be described as hydrophilic, hydrophobic, salts ofhydrophilic or hydrophobic amino acids, or any combination thereof.Preferred hydrophobic amino acids for use in the present invention areiso-leucine, phenylalanine, leucine, and valine. Further, hydrophilicamino acids, such as glycine, aspartate and glutamate can be used in thegranule. Ultimately, any amino acid, and any amino acid in combinationwith another amino acid, can be employed in the present invention toenhance the solubility of a drug. For a detailed list of amino acidsthat can be used in the present invention and the hydropathy of each,see Albert L. Lehninger et al., Principles of Biochemistry 113 (2nd ed.Worth Publishers 1993).

[0036] The type and amount of amino acid may be chosen depending on thedesired drug load, desired rate of drug release, and the solubility ofthe drug. The amino acid in the dosage form is typically between 4% and45% of the total dosage form weight. However, the amount of amino acidis preferably between 11% and 29% by weight of the total dosage form.

[0037] The granules may optionally be blended with a coating material,for example magnesium stearate or other hydrophobic derivatives ofstearic acid. The amount of coating material used can vary from 1% to 3%of the total weight of the dosage form. Normally, magnesium stearate isused to facilitate processing, for example as a flow aid, but in thepresent invention magnesium stearate has the additional benefit ofretarding dissolution, due to the hydrophobic nature of the coatingmaterial. Therefore, magnesium stearate can be used to further adjustthe solubility of the dosage form and further retard drug release fromthe granules.

[0038] To enhance the mechanical properties and/or to influence the drugrelease rate further, the granules may also contain small amounts ofinert pharmaceutical fillers and binders/granulating agents as isconventional to the art. Examples of inert pharmaceutical fillersinclude: lactose, sucrose, maltose, maltodextrins, dextrins, starch,microcrystalline cellulose, fructose, sorbitol, di-and tri-calciumphosphate. Examples of granulating agents/binders include starch,methylcellulose, hydroxy propyl- or hydroxypropylmethyl cellulose,sodium carboxymethyl cellulose, or poly-vinyl pyrrolidone, gum accaciatragacanth and sucrose. Other suitable fillers may also be employed asunderstood by one of skill in the art. Depending on the physical and/orchemical properties of the drug, a wet granulation procedure (usingeither an aqueous or organic granulating fluid) or a dry granulationprocedure (e.g. slugging or roller compaction) can be employed.

[0039] After the granulation of the pharmaceutically active compound,intragranular polymer, amino acids, and optionally fillers andhydrophobic coating materials, the granule is then blended with anddispersed within an extragranular polymer.

[0040] The extragranular polymer may be one or more of the following:polyethylene oxide, a galactomannan polysaccharide such as hydroxypropylguar, guar gum, locust bean gum, pectin, gum accacia, gum tragacanth,karaya gum, cellulose ethers such as hydroxypropylmethyl cellulose(HPMC), as well as other gums and cellulose ethers to be chosen by oneof skill in the art for properties consistent with the teaching of thisinvention. The extragranular polymer is preferably a galactomannanpolysaccharide, most preferably guar gum (with a viscosity range of75-6000 cps for a 1% solution at 25° C. in water and a particle size10-300μm). As noted above, it is important that the extragranularpolymer hydrates rapidly and achieves a high level of viscosity in ashorter period of time relative to the intragranular polymer.

[0041] The difference in hydration rates between the extragranularpolymer and intragranular polymer is achieved by three principle means,(1) by choosing polymers based on differences in particle size, (2) bychoosing polymers based on differences in molecular weight and chemicalcomposition and (3) by choosing polymers based on a combination of (1)and (2). Although this disclosure focuses primarily on polymers chosenfor differences in particle size, it is possible to achieve the resultsof this invention by using an intragranular polymer with a differentmolecular weight and/or chemical composition than the extragranularpolymer. For example, polyethylene oxide may be used as theintragranular polymer and guar gum as the extragranular polymer.

[0042] Particle size is an important characteristic of commercial guargum because coarser particles ensure rapid dispersion, while finerparticles are ideal for fast hydration. Therefore, in order to achievethe desired result of the present invention, the finer particles areused for the extragranular polymer and less fine particles are used forthe intragranular polymer particles. The brochure by HERCULESIncorporated, entitled “Supercol® Guar Gum, 1997” contains the typicalproperties of guar gum of different grades and particles sizes. Theinformation in the brochure is readily obtainable to one of ordinaryskill in the art and a chart showing the different characteristics ofguar gum is included here for completeness: Peak Vis- Grade of Vis-cosity % Supercol Form Mesh cosity Rate in 15 min.* Dispersibility G3-SCoarse 60 4,000 Slow 40 Excellent G2-S Medium 80 4,500 Mod- 50 ExcellentCoarse erate GF Medium 150 4,500 Fast 70 Very good Fine U Fine 200 5,100Very 90 Fair Fast (requires care) US Fine 200 5,500 Very 90 Fair Fast(requires care) K-1 Medium 150 1,200 Slow 30 Fair Fine (requires care)

[0043] For example, Guar U achieves 90% of its maximum viscosity (5100cps) in 15 minutes. It is therefore possible to use Guar U as therapidly hydrating extragranular polymer and Guar G3, which achieves 40%of peak viscosity (4000 cps) in 15 minutes, as the less rapidlyhydrating and less viscous intragranular polymer. Other rapidlyhydrating extragranular polymers which may be used include: polyethyleneoxide (PEO), cellulose ethers and polysaccharides such as hydroxypropylguar, pectin, gum accacia and tragacanth, karaya gum, mixtures of theaforementioned polymers and any other polymers to be chosen by one ofskill in the art for properties consistent with the teaching of thisinvention. The amounts and the types of extragranular polymer are chosendepending on the desired drug load, rate of drug release and drugsolubility. A range of about 4-47% (by total tablet weight) ofextragranular polymer has been found to be feasible, but a range ofabout 15%-47% is particularly preferred.

[0044] The present invention is capable of containing a therapeuticamount of a pharmaceutically active compound, preferably up to about 75%of the total dosage form weight. With this drug load, the tableted oralextended release dosage form approximates a linear release profile, witha minimal, or elimination of, burst effect. However, if desired by askilled artisan, the extragranular polymer may contain additionalamounts of the pharmaceutically active compound to achieve more rapiddrug release or an induced burst effect, as well as contain amino acidsto mediate dissolution of the pharmaceutically active compound, asdescribed above.

[0045] The tableted oral extended release dosage form optionally may becoated with polymers, plasticizers, opacifiers, and colourants as isconventional in the art.

[0046] The tableted oral extended release dosage form of the presentinvention is typically prepared as follows.

[0047] Appropriate amounts of intragranular polymer, pharmaceuticallyactive compound, and amino acids are weighed. After weighing, eachingredient may optionally be passed through a mesh screen todeagglomerate the constituents into fine powders. Preferably, a #30 meshscreen is used.

[0048] The powders are then mixed in a mixer, suitably in a twin shellV-mixer (Patterson-Kelly, East Stroudsburg, Pa.) until the componentsare evenly mixed, typically about 20 minutes. Optionally, inert fillersmay be added during the mixing step.

[0049] The mixture is then added to the mixing bowl of a planetarymixer. A granulating fluid such as water, iso-propanol, a mixture ofwater and iso-propanol, or a pharmaceutically acceptable solvent isadded where necessary. The granulating fluid is added while continuouslymixing until a coherent wet mass is formed. Typically, coherent wet massformation takes about 10 minutes. Preferably, the wet mass is hydratedfor an additional 15 minutes while constantly stirring.

[0050] The wet mass is then passed through a sieve, typically a 1 mmstainless steel sieve, to form granules. The sieve is typically mountedon an oscillating granulator, such as a granulator from Erweka,Heusenstamm, Germany.

[0051] Alternatively, granulation may be achieved by a dry granulationprocess, for example slugging or roller compaction.

[0052] The granules are then dried. Typically, the granules are dried ontrays, for example in a vacuum oven at 50° C. for about 3.5 hours oruntil the loss on drying is less than 1.5% of the granule weight.

[0053] An amount of extragranular polymer is then added to the granules.Typically, sufficient extragranular polymer is added to achieve anamount of about 4% to about 47% of the total final tablet weight.Preferably, sufficient amounts are added to achieve about 15% to about47% of the total final tablet weight.

[0054] The extragranular polymer and granules are then blended,typically in a twin shell V-mixer, preferably for at least 15 minutes. Asmall amount (about 0.5% to about 1%) of a lubricant, typicallymagnesium stearate, may optionally be added to the mixture. This may beaccomplished by sieving the lubricant through a fine screen or othermethods as is apparent to one of skill in the art.

[0055] Prior to compression, additional amounts of lubricant mayoptionally be added. This is done to induce greater hydrophobicity inthe tablet. Typical levels added may be about 1% to about 3% of thetotal tablet weight.

[0056] Also, a flow-promoting agent such as 1-2% talc or colloidalsilicon dioxide can be added to the mixture immediately before addingthe lubricant. These agents ensure the optimal flow of the powdermixture from the hopper, into the feeding mechanism and die cavities ofthe tablet press. Uniform fast flow under gravity is essential to ensureuniform filling of die cavities and by implication uniform tabletweights and dosages. However, the granules of the present inventiontypically have adequate flow properties, thus obviating this commonlyused industry practice.

[0057] The final mix is suitable for compression on a commercial largescale tablet press. Preferably, compression may be done on a rotarypress, such as the Stokes B2 rotary press, or on smaller lab scalepresses such as Mannesty F3-single punch press and the Carver manuallyoperated hydraulic press. The settings on the press should be set suchthat compaction pressure should be in the range of about 160-180 MPa.This yields tablets with hardness of about 70-100 N.

[0058] While this invention has been described with reference tospecific embodiments, it is not necessarily limited thereto.Accordingly, the appended claims should be construed to encompass notonly those forms and embodiments of the invention specifically describedabove, but to such other forms and embodiments as may be devised bythose skilled in the art without departing from its true spirit andscope.

EXAMPLES AND TABLE

[0059] The formulations described below have been prepared in accordancewith the general procedures described above. In these formulations, an *indicates that a component has been added by dry blending, i.e. it ispresent as an extragranular excipient.

Example 1 Example 1a

[0060] (FIG. 1a) illustrates the effect of adding an intragranular aminoacid to a typical verapamil formulation containing guar as anintragranular and extragranular polymer. Control Component FormulationWith Glycine With Aspartate Verapamil HCl 120 mg 120 mg 120 mg Glycine — 54 mg — Aspartic acid — —  54 mg Guar Gum (G)  54 mg  54 mg  54 mg GuarGum (U)*  72 mg*  72 mg*  72 mg* Total tablet weight 246 mg 300 mg 300mg

Example 1b

[0061] (FIG. 1b) Illustrates the effect of adding amino acid to a dryblended, non granulated verapamil formulation, in which the verapamilHCl was not granulated, but blended with the two polymers prior tocompression into a tablet. Component Control Formulation With GlycineVerapamil HCl 120 mg 120 mg Glycine —  54 mg Guar Gum (G)  54 mg  54 mgGuar Gum (U)*  72 mg*  72 mg* Total tablet weight 246 mg 300 mg

Example 2 Example 2a

[0062] (FIG. 2a) Illustrates the effect of a combination of iso-leucineand glycine in a formulation containing nifedipine (a highly insolubledrug) versus a formulation containing no iso-leucine and glycine.Component Test Formulation Control Nifedipine  30 mg 30 mg Glycine  24mg — Iso-Leucine  24 mg — Guar Gum (G)  22 mg 22 mg Guar Gum (G)*  22mg* 22 mg* Total tablet weight 122 mg 74 mg

Example 2b

[0063] (FIG. 2b) Illustrates the effect of a combination of iso-leucineand glycine in a dry blended, non-granulated formulation containingnifedipine (a highly insoluble drug) versus a similar formulationcontaining no iso-leucine and glycine. Component Test FormulationControl Nifedipine  30 mg 30 mg Glycine  24 mg — Iso-Leucine  24 mg —Guar Gum (G)  22 mg 22 mg Guar Gum (G)*  22 mg* 22 mg* Total tabletweight 122 mg 74 mg

[0064] TABLE 1 AMINO ACID HYDROPHOBIC VALUE CHARACTERIZATION Isoleucine1.83 Strongly Hydrophobic Leucine 1.80 Phenylalanine 1.69 Tryptophan1.35 Valine 1.32 Methionine 1.10 Moderately Hydrophobic Proline 0.84Cysteine 0.76 Tyrosine 0.39 Weakly Hydrophobic Alanine 0.35 Glycine 0Neutral, Balanced Threonine −0.27 Weakly Hydrophilic Serine −0.63Histidine −0.65 Glutamine −0.93 Moderately Hydrophilic Asparagine −0.99Ornithine −1.50 Strongly Hydrophulic Lysine −1.54 Aspartic acid −2.15

What is claimed is:
 1. An oral extended release dosage form comprising:(1) a plurality of granules comprising (a) a pharmaceutically activecompound; (b) at least one amino acid; and (c) an intragranular polymer;said intragranular polymer comprising 4% to 45% of the total dosage formby weight and, (2) a hydrophilic extragranular polymer in which saidgranules are dispersed, said extragranular polymer comprising 4% to 47%of the total dosage form by weight and being more rapidly hydrating thansaid intragranular polymer, wherein: the amino acid is selected forhydropathy characteristics depending on solubility characteristics ofthe active compound and comprises 11% to 29% of the total dosage form byweight; when said active compound is at least sparingly soluble, saidamino acid has a relatively equal balance between hydrophobic andhydrophilic components or is relatively more hydrophilic; and when saidactive compound is less than sparingly soluble, said amino acid is acombination of at least two amino acids, one of which is moderately orstrongly hydrophobic, the other of which is relatively more hydrophilic.2. The oral extended release dosage form of claim 1, wherein saidpharmaceutically active compound release profile approximates azero-order release profile.
 3. The oral extended release dosage form ofclaim 1, wherein said tableted oral extended release dosage formachieves about 100% release of said pharmaceutically active compound. 4.The oral extended release dosage form of claim 1, wherein release ofsaid pharmaceutically active compound takes between 12 and 24 hours toreach about 100% release.
 5. The oral extended release dosage form ofclaim 1, wherein said intragranular polymer comprises at least one ofthe following: polyvinyl acetate, a galactomannan polysaccharideselected from the group consisting of hydroxypropyl guar, guar gum,locust bean gum, pectin, gum accacia, tragacanth, karaya gum, orcellulose ethers.
 6. The oral extended release dosage form of claim 5wherein said intragranular polymer is a galactomannan polysaccharide andthe extragranular polymer is guar gum.
 7. The oral extended releasedosage form of one of claim 6, wherein said intragranular polymer isguar gum having a higher molecular weight, larger particle size, orboth, than the extragranular polymer.
 8. The oral extended releasedosage form of claim 1, wherein said amino acid is selected from thegroup consisting of: a) α-amino acids b) β-amino acids c) a combinationof α- and β-amino acids.
 9. The oral extended release dosage form ofclaim 8, wherein said α-amino acid is at least one member selected fromthe group consisting of glycine, alanine, valine, leucine, iso-leucine,phenylalanine, proline, aspartic acid, glutamic acid, lysine, arginine,histidine, serine, threonine, cysteine, asparagine and glutamine. 10.The oral extended release dosage form of claim 8, wherein saidcombination of α and β amino acids comprises β-alanine and at least oneα-amino acid selected from the group consisting of glycine, alanine,valine, leucine, iso-leucine, phenylalanine, proline, aspartic acid,glutamic acid, lysine, arginine, histidine, serine, threonine, cysteine,asparagine, and glutamine.
 11. The oral extended release dosage form ofclaim 1, wherein said amino acid is selected from the group consistingof: a) a balanced amino acid having a relatively equal balance betweenhydrophobic and hydrophilic components or a relatively more hydrophilicamino acid, or b) a combination of (i) a balanced amino acid or arelatively more hydrophilic amino acid and (ii) a hydrophobic aminoacid.
 12. The oral extended release dosage form of claim 11, whereinsaid balanced amino acid comprises glycine.
 13. The oral extendedrelease dosage form of claim 12, comprising glycine and a hydrophobicamino acid selected from iso-leucine, valine, and phenylalanine.
 14. Theoral extended release dosage form of claim 1, wherein said granule isblended with a hydrophobic coating material.
 15. The oral extendedrelease dosage form of claim 14, wherein said hydrophobic coatingmaterial is magnesium stearate.
 16. The oral extended release dosageform claim 15, wherein said hydrophobic coating material is 1% to 3% ofthe total dosage form weight.
 17. The oral extended release dosage formof claim 1, wherein said granule optionally contains conventionaltableting additives selected from at least one of lactose, sucrose,maltose, maltodextrins, dextrins, starch, microcrystalline cellulose,fructose, sorbitol, di-and tri -calcium phosphate, starch,methylcellulose, hydroxy propyl- or hydroxypropyl methyl cellulose,sodium carboxymethyl cellulose, or poly vinyl pyrrolidone, gum accaciatragacanth and sucrose.
 18. The oral extended release dosage form ofclaim 17, wherein said extragranular polymer comprises guar gum.
 19. Theoral extended release dosage form of claim 1, wherein saidpharmaceutically active compound is present in the amount of up to 75%of the total dosage form weight.
 20. The oral extended release dosageform of claim 1, wherein said extragranular polymer contains apharmaceutically active compound.
 21. The oral extended release dosageform of claim 1, wherein said extragranular polymer contains aminoacids.
 22. The oral extended release dosage form of claim 1, whereinsaid dosage form is coated with at least one of the following: (a)polymer, (b) plasticizer, (3) opacifier, and (4) colourant.
 23. Aprocess of making a tableted oral extended release dosage form, thesteps comprising: a. Mixing (a) an amount of pharmaceutically activecompound, (b) an intragranular polymer, and (c) at least one amino acidto form a first mixture, b. Forming said first mixture into granules, c.Blending an extragranular polymer with said granules, and d. Compressingthe resulting blend into simple monolithic tablets, wherein saidgranules are dispersed in and substantially surrounded by saidextragranular polymer, said extragranular polymer is more rapidlyhydrating than said intragranular polymer, and wherein. the amino acidis selected for hydropathy characteristics depending on solubilitycharacteristics of the active compound, when said active compound is atleast sparingly soluble, said amino acid has a relatively equal balancebetween hydrophobic and hydrophilic components or is relatively morehydrophilic; when said active compound is less than sparingly soluble,said amino acid is a combination of at least two amino acids, one ofwhich is strongly hydrophobic, the other of which is relatively morehydrophilic.